Protein & Cell (Aug 2020)
Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2
- Rui Xiong,
- Leike Zhang,
- Shiliang Li,
- Yuan Sun,
- Minyi Ding,
- Yong Wang,
- Yongliang Zhao,
- Yan Wu,
- Weijuan Shang,
- Xiaming Jiang,
- Jiwei Shan,
- Zihao Shen,
- Yi Tong,
- Liuxin Xu,
- Yu Chen,
- Yingle Liu,
- Gang Zou,
- Dimitri Lavillete,
- Zhenjiang Zhao,
- Rui Wang,
- Lili Zhu,
- Gengfu Xiao,
- Ke Lan,
- Honglin Li,
- Ke Xu
Affiliations
- Rui Xiong
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology
- Leike Zhang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences
- Shiliang Li
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology
- Yuan Sun
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences
- Minyi Ding
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology
- Yong Wang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University
- Yongliang Zhao
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University
- Yan Wu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences
- Weijuan Shang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences
- Xiaming Jiang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences
- Jiwei Shan
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology
- Zihao Shen
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology
- Yi Tong
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology
- Liuxin Xu
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology
- Yu Chen
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University
- Yingle Liu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University
- Gang Zou
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Dimitri Lavillete
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Zhenjiang Zhao
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology
- Rui Wang
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology
- Lili Zhu
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology
- Gengfu Xiao
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences
- Ke Lan
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University
- Honglin Li
- Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology
- Ke Xu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University
- DOI
- https://doi.org/10.1007/s13238-020-00768-w
- Journal volume & issue
-
Vol. 11,
no. 10
pp. 723 – 739
Abstract
Abstract Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC50 of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
Keywords
- de novo pyrimidine biosynthesis
- DHODH inhibitors
- SARS-CoV-2
- influenza viruses
- virus replication
- immuno-regulation